Differentiated thyroid cancer (DTC) generally has a favorable prognosis, and radioactive iodine (RAI) therapy is typically used for metastatic DTC that continues to progress and poses life-threatening risks. However, resistance to RAI in metastatic DTC significantly impairs treatment effectiveness. This study aims to identify potential compounds that may influence RAI efficacy. We conducted untargeted metabolomics on pre-treatment serum samples from 42 RAI-refractory DTC (RAIR-DTC) patients and 52 RAI-sensitive patients. The results revealed significantly elevated levels of two per- and polyfluoroalkyl substances (PFAS), PFDA and PFNA, in RAI-resistant patients. This accumulation was significantly negatively correlated with the expression of the sodium-iodide symporter (NIS), which reflects the differentiation status and iodide uptake capability of thyroid cancer. Furthermore, high levels of PFDA and PFNA exposure were significantly associated with poor prognosis in patients undergoing RAI therapy. In vivo exposure simulations in a murine model showed that PFAS exposure significantly increased the malignant progression of thyroid cancer, reduced iodine uptake ability, and promoted dedifferentiation. Overall, these findings provide novel insights into the development of RAIR-DTC, highlighting the importance of continuous monitoring and control of PFAS exposure in cancer patients.
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